CN110694076B - Hydroxychloroquine amphiphilic polymer prodrug, preparation method and application thereof - Google Patents
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Abstract
The invention discloses a hydroxychloroquine amphiphilic polymer prodrug, which is composed of hydrophilic polyethylene glycol monomethyl ether and a hydrophobic hydroxychloroquine polymer, wherein the hydroxychloroquine polymer is bonded on the polyethylene glycol monomethyl ether through a breakable chemical bond, and the hydroxychloroquine amphiphilic polymer prodrug can be self-assembled into nanoparticles with the particle size of 20-300nm in water, so that the pharmacokinetic behavior of free hydroxychloroquine is improved, and the nanoparticles have remarkable long-circulating characteristic.
Description
Technical Field
The invention belongs to the field of prodrugs and preparation thereof, and particularly relates to a hydroxychloroquine amphiphilic polymer prodrug, a preparation method and application thereof.
Background
Hydroxychloroquine (shown as formula A) is a 4-aminoquinoline antimalarial, and can be used for treating systemic lupus erythematosus, rheumatoid arthritis and other immune diseases. The hydroxychloroquine is clinically used as oral hydroxychloroquine sulfate, the pharmacology and action mechanism of the hydroxychloroquine sulfate are similar to those of chloroquine, but the toxicity of the hydroxychloroquine sulfate is lower than that of the chloroquine. The structural difference between hydroxychloroquine and chloroquine is that the N-ethyl group at the end of the side chain of chloroquine is hydroxylated and therefore named hydroxychloroquine.
In recent years, more and more researches show that hydroxychloroquine and chloroquine have various biological and pharmacological activities, and have the effects of regulating immunity, resisting blood coagulation, resisting infection, resisting tumor, preventing thrombus, reducing blood fat and the like besides antimalarial and anti-inflammatory effects. In the anti-tumor field, hydroxychloroquine and chloroquine are used as autophagy inhibitors, which can enhance the killing effect of anticancer drugs on cancer cells and can also improve the treatment effects of radiotherapy, photodynamic therapy and the like (Combined autophagy and proteosome information: A Phase 1 Phase of hydroxhloroquine and bortezomib in tissues with replayed/reconstructed tissue bacteria 2014; 10: 1380-90; Combined MTOR and autophagy information: Phase I Phase of hydroxhloroquine and temporolimus in tissues with synthesized soluble tissues and cell analytes 20149: 1369: 10: 1391-402; Phase I Phase of hydroxhloroquine and hydrogel in tissues with adsorbed tissues and cell 20149: 1369). At present, a plurality of preclinical and clinical tests are carried out, so that hydroxychloroquine and chloroquine have increasingly wide application values in clinic.
Because the hydroxychloroquine drugs have no selectivity in the distribution in vivo, systemic toxicity of organisms, such as retinal change, corneal change, skin diseases, gastrointestinal adverse reactions and the like, can be caused when high dose is used only for enhancing the curative effect, and in order to relieve the adverse effect of the hydroxychloroquine drugs on the bodies, the drug molecules and the nano-carrier are compounded by using the biological nano-technology to form the nano-drug, so that the pharmacokinetics and tissue distribution of the drug can be improved, the curative effect is improved, and the toxic and side effects are reduced. The paclitaxel-albumin nanoparticle ABRAXANE, adriamycin liposome DOXIL and other classical nano dosage forms are in clinical application, and a plurality of nano drugs are in clinical test stages, so people hope to improve the pharmacology of hydroxychloroquine by a nanotechnology and expand the application range of the drugs.
The publication No. CN107375199A discloses a polymeric chloroquine nanogel delivery system, which takes polysaccharide as a framework and consists of polymeric chloroquine and an anti-tumor drug wrapped in a particle, and the nanogel delivery system can inhibit tumor growth and metastasis simultaneously and effectively treat malignant tumors.
The publication No. CN105924641A discloses a preparation method of hydroxychloroquine sulfate polyglutamic acid polymer, which is formed by esterification reaction of hydroxychloroquine and polyglutamic acid, and can improve the slow release effect of the drug, reduce the drug taking frequency, simultaneously deliver the drug to the focus part and improve the curative effect of hydroxychloroquine in treating discoid lupus erythematosus and systemic lupus erythematosus.
At present, hydroxychloroquine is mainly connected to polyglutamic acid or polysaccharide through chemical reaction, but the reaction time of the reaction is long, the drug loading rate is not easy to control, and when the content of hydroxychloroquine is too high, the water solubility of the whole system is also poor.
Disclosure of Invention
The invention provides a hydroxychloroquine amphiphilic polymer prodrug, which can be self-assembled into nanoparticles (or called micelles or vesicles), can load various hydrophobic drugs due to the existence of the hydroxychloroquine in a hydrophobic core, realizes in vivo long circulation, reduces the binding capacity of the hydroxychloroquine and erythrocytes, fully exerts the pharmacological action of the hydroxychloroquine, and greatly improves the pharmacokinetic behavior of the hydroxychloroquine.
The hydroxychloroquine amphiphilic polymer prodrug comprises a hydrophobic end formed by polymerized hydroxychloroquine and a hydrophilic end formed by polyethylene glycol monomethyl ether, wherein intermolecular polymerization can be realized between the hydrophilic end and the hydrophobic end in a mode of forming degradable chemical bonds through active free radical polymerization, and the number average molecular weight of the polyethylene glycol monomethyl ether is 1000-50000; the number average molecular weight of the hydroxychloroquine polymer is 500-50000.
The living free radical polymerization mode is one or more of reversible addition-fragmentation chain transfer polymerization (RAFT), Atom Transfer Radical Polymerization (ATRP), solution polymerization and Ring Opening Metathesis Polymerization (ROMP).
The degradable chemical bond is one of ester bonds, carbonate bonds, disulfide bonds, thioether bonds, urea bonds, hydrazone bonds, urethane bonds and the like, and can realize in-vivo and in-vitro multiple responsive release.
Preferably, the hydroxychloroquine amphiphilic polymer prodrug (abbreviated as PHCQ) is a compound having a structure shown in formula I below:
in the formula I, n is 22-1136; m is 1-100; x is a structural formula shown in formulas II and III.
The hydroxychloroquine amphiphilic polymer prodrug can be self-assembled to form nanoparticles, various hydrophobic drugs can be loaded due to the existence of hydroxychloroquine in a hydrophobic core, and meanwhile, the water solubility of the hydroxychloroquine amphiphilic polymer prodrug is increased due to the introduction of the polyethylene glycol monomethyl ether, and the toxicity to normal tissues is reduced.
The invention also provides a preparation method of the hydroxychloroquine amphiphilic polymer prodrug, which has the advantages of high yield, simple method and suitability for industrial production.
The preparation method of the hydroxychloroquine amphiphilic polymer prodrug comprises the following steps:
(1) dissolving acryloyl chloride compounds, acrylic anhydride compounds or hydroxyethyl acrylate compounds and free hydroxychloroquine in an organic solvent, and obtaining hydroxychloroquine compound monomer structures shown in formulas II and III under the synergistic action of a condensation reagent and an acylation catalyst:
the hydroxyl chloroquine compound monomer formula II containing ester group or lipid group;
the hydroxyl chloroquine compound containing disulfide group has a monomer formula III;
(2) dissolving polyethylene glycol monomethyl ether and a micromolecule chain transfer agent PETTC into an organic solvent, and reacting under the synergistic action of a condensation reagent and an acylation catalyst to obtain the macromolecular chain transfer agent (PEG-PETTC) of the polyethylene glycol monomethyl ether-chain transfer agent, wherein the macromolecular chain transfer agent is a compound with a structure shown in the following formula IV:
n＝22～1136；
(3) and (2) polymerizing the hydroxychloroquine compound monomer (formula II or formula III) obtained in the step (1) and a macromolecular chain transfer agent (formula IV) of a polyethylene glycol monomethyl ether-chain transfer agent under the action of an initiator to generate a hydroxychloroquine amphiphilic polymer prodrug shown in the formula I through active free radical polymerization, wherein the polymerization temperature is 60-80 ℃.
In the step (1) or (2), the condensation reagent is one or more of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), N' -Dicyclohexylcarbodiimide (DCC) and Diisopropylcarbodiimide (DIC).
In the step (1) or (2), the acylation catalyst is one or more of 4-N, N-Dimethylpyridine (DMAP), 1-hydroxybenzotriazole (HOBt), pyridine and triethylamine.
In the step (3), the initiator is one of Azobisisobutyronitrile (AIBN), 4 '-azobis (4-cyanovaleric acid) (V501) and 1, 1' -azobis (1-cyclohexanecarbonitrile) (ACCN).
In the step (2), due to the fact that the steric hindrance of the polyethylene glycol monomethyl ether is large, the reaction time is preferably 48-72 hours.
In the step (1) or (2), the organic solvent is one or more of Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), Dichloromethane (DCM), dioxane, methanol, ethanol, tetrahydrofuran, cyclohexane, toluene and anisole.
The invention also provides a method for preparing nano particles (PHCQ-NP) by the hydroxychloroquine amphiphilic polymer prodrug, which comprises a dialysis method, a solvent volatilization method, a thin film hydration method and a coprecipitation method.
Preferably, the method is a dialysis method, wherein the hydroxychloroquine amphiphilic polymer prodrug is dissolved in an organic solvent, slowly and dropwise added into deionized water with the volume of 1-10 times that of the organic solvent, stirred for 10-20 minutes, and dialyzed by using a semipermeable membrane to remove the organic solvent, so that the hydroxychloroquine amphiphilic polymer prodrug nanoparticle solution is obtained.
The organic solvent comprises one of N, N' -dimethylformamide, dimethyl sulfoxide, methanol, ethanol and dioxane, and dimethyl sulfoxide is further preferable in order to ensure the particle size distribution, experimental repeatability and operability of the prepared nanoparticles.
The nano particles have a particle size range of 20-300nm, uniform particle size distribution and a drug loading rate of 50-80%.
The particle size of the nano-particles can be controlled by the type of the organic solvent, the concentration of the polymer and the dropping speed.
Different from the prior art, the invention has the beneficial effects that:
(1) in the hydroxychloroquine amphiphilic polymer prodrug provided by the invention, due to the strong hydrophobicity of the hydroxychloroquine polymer, the hydrophilic molecule polyethylene glycol monomethyl ether is introduced, so that the prepared hydroxychloroquine amphiphilic polymer prodrug has a remarkable long-circulating effect compared with free hydroxychloroquine, the water solubility of the drug is improved, the pharmacokinetic behavior of hydroxychloroquine is greatly improved, the binding capacity of hydroxychloroquine and erythrocytes is reduced, the toxic and side effects on normal cells are reduced, and the pharmacological effect of hydroxychloroquine is fully exerted.
(2) The hydroxychloroquine amphiphilic polymer prodrug nanoparticle can load various hydrophobic drugs including camptothecin and derivatives thereof, paclitaxel, adriamycin, bortezomib and various negatively charged drug molecules due to the existence of the hydroxychloroquine in the hydrophobic core, so that hydroxychloroquine drugs have wide clinical treatment effects, are often combined with various anti-cancer drugs and immunomodulators for synergistic treatment particularly in tumor treatment, and can load negatively charged nucleic acids including DNA, mRNA, siRNA and the like due to the slightly positive property of the hydroxychloroquine, and are used for gene delivery and synergistic treatment.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a polyethylene glycol monomethyl ether chain transfer agent PEG-PETTC;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of intermediate DTMA;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of hydroxychloroquine monomer DTMAHCQ;
FIG. 4 is a NMR hydrogen spectrum of PHCQ;
FIG. 5 is a gel permeation chromatography characterization of PHCQ;
FIG. 6 is a graph of dynamic light scattering of PHCQ-NP;
FIG. 7 is a transmission electron micrograph of PHCQ-NP;
FIG. 8 is a graph of the in vitro release of PHCQ-NP;
FIG. 9 is the drug-time curve and pharmacokinetic parameters of PHCQ-NP in blood.
Detailed Description
The present invention will be further described with reference to the following examples, in which the experimental methods used are, unless otherwise specified, conventional ones, and materials, reagents and the like used in the examples are, unless otherwise specified, commercially available.
Example (b):
synthesis of the hydroxychloroquine amphiphilic polymer prodrug:
this example synthesizes a prodrug of a hydroxychloroquine amphiphilic polymer with disulfide bond linkage, which has a molecular weight of about 10000 and a uniform molecular weight distribution, wherein the molecular weight of the polyethylene glycol monomethyl ether is 5000.
1. Synthesis of polyethylene glycol monomethyl ether chain transfer agent (PEG-PETTC):
4g of polyethylene glycol monomethyl ether (molecular weight of 5000, 0.8mmol) is taken, the water is removed by refluxing, 100mL of dichloromethane is added for dissolution after spin-drying, 5 equivalents of 4-cyano-4- (2-phenylethane sulfanyl thiocarbonyl) sulfanyl pentanoic acid (PETTC) and 0.5 equivalent of 4-dimethylamino pyridine (DMAP) are added, 5 equivalents of Dicyclohexylcarbodiimide (DCC) Dichloromethane (DCM) solution are added dropwise under the ice bath condition, the ice bath is removed after the dropwise addition is finished, and the stirring is carried out for 48 hours at room temperature. The reaction was concentrated under reduced pressure, precipitated three times with ice, anhydrous ethanol and dried in vacuo to give the product (3.6g, 90% yield). The nuclear magnetic resonance hydrogen spectrum of the polyethylene glycol chain transfer agent PEG-PETTC is shown in figure 1.
The peaks of the nuclear magnetic resonance hydrogen spectrogram of PEG-PETTC are detected as follows:1H NMR(400MHz,CDCl3)δ7.36–7.30(m,3H),7.26–7.22(m,2H),4.29–4.24(m,2H),3.65(m,450H),3.38(s,3H),3.04–2.96(m,2H),2.70–2.62(m,2H),2.58–2.48(m,1H),2.44–2.35(m,1H).
2. synthesis of disulfide-bonded hydroxychloroquine monomer DTMAHCQ
Synthesis of intermediate DTMA: 20g (0.095mol) of 3,3' -dihydroxylic acid (DTDPA), 13.6g (0.1mol) of hydroxyethyl methacrylate (HEMA) and 1.74g (0.014mol) of 4-dimethylaminopyridine were blended in 200mL of dichloromethane, and 20g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was dissolved in 200mL of dichloromethane, and added dropwise to the mixture under ice-bath conditions, followed by stirring at room temperature overnight. Washing the reaction solution with water for three times, washing with 1M HCl solution for three times, washing with saturated NaCl solution for two times, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain crude product, purifying the crude product with n-hexane/ethyl acetate eluent through column to obtain product named as DTMA, and the nuclear magnetic resonance hydrogen spectrogram of DTMA is shown in figure 2.
The nuclear magnetic resonance hydrogen spectrogram peaks of the intermediate product DTMA are detected as follows:1H NMR(400MHz,CDCl3)δ6.14(s,1H),5.65–5.58(m,1H),4.37(s,4H),3.00–2.84(m,4H),2.88–2.61(m,4H),1.95(s,3H).
synthesis of DTMAHCQ: 1.7g (0.05mol) of desalted hydroxychloroquine, 1.6 g (0.05mol) of DTMA and 90mg (0.0075mol) of 4-dimethylaminopyridine were dissolved in 50mL of dichloromethane. 1.4g (0.075mol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was dissolved in 20mL of dichloromethane and added dropwise to the mixture under ice bath conditions. Stir at room temperature overnight. The reaction solution is washed with water for three times, washed with saturated NaCl solution for two times, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography using dichloromethane/methanol eluent and the product was named DTMAHCQ. The NMR spectrum of DTMAHCQ is shown in FIG. 3.
The nuclear magnetic resonance hydrogen spectrogram peaks of the DTMAHCQ are detected as follows:1H NMR(400MHz,CDCl3)δ8.50(d,J＝5.5Hz,1H),7.95(d,J＝2.1Hz,1H),7.72(d,J＝9.0Hz,1H),7.35(dd,J＝8.9,2.1Hz,1H),6.43(d,J＝5.5Hz,1H),6.13(s,1H),5.68–5.56(m,1H),5.22(d,J＝7.2Hz,1H),4.35(s,4H),4.17(t,J＝6.2Hz,2H),3.72(dd,J＝12.0,5.5Hz,1H),2.89(td,J＝7.1,3.6Hz,4H),2.73(dt,J＝17.8,6.6Hz,6H),2.61–2.41(m,4H),1.95(s,3H),1.81–1.51(m,4H),1.33(d,J＝6.3Hz,3H),1.01(t,J＝7.1Hz,3H).
3. synthesis of disulfide-bonded hydroxychloroquine amphiphilic Polymer prodrug PHCQ
500 mg (0.1mmol) of polyethylene glycol chain transfer agent PEG-PETTC, 500 mg (0.78mmol) of hydroxychloroquine monomer DTMAHCQ and 5mg (0.03mmol) of azobisisobutyronitrile are dissolved in 5mL of dioxane and placed in a polymerization bottle. The nitrogen is bubbled for 30min to fully remove oxygen, the polymerization bottle is closed, and the mixture is placed in an oil bath kettle at the temperature of 70 ℃ for reaction for 24 h. After the reaction was completed, the reaction was terminated with liquid nitrogen. The reaction was precipitated 2 times with glacial ethanol and 2 times with diethyl ether and dried under vacuum to give 665mg (66.5% yield) of the product, which was designated PHCQ. The NMR spectrum of the polymer PHCQ is shown in FIG. 4.
The peaks of the nuclear magnetic resonance hydrogen spectrogram of PHCQ are detected as follows:1H NMR(400MHz,DMSO)δ8.35(s,12H),7.75(s,6H),7.40(s,6H),7.25(s,3H),6.90(s,6H),6.45(s,6H),4.37–3.93(m,42H),3.51(s,460H),3.24(s,3H),2.95–2.52(m,70H),2.41(s,24H),1.86(s,6H),1.52(dd,J＝91.7,31.8Hz,30H),1.23(d,J＝27.7Hz,22H),0.82(d,J＝40.3Hz,36H).
the synthetic route is as follows:
hydroxychloroquine amphiphilicityThe gel permeation chromatogram of polymer prodrug PHCQ is shown in figure 5, compared with polyethylene glycol chain transfer agent PEG-PETTC, the peak emergence time of hydroxychloroquine polymer is obviously shifted, and the monodispersed polymer can be obtained by controlling the reaction condition, wherein the number average molecular weight Mn of the polymer is 2.58 × 104Weight average molecular weight Mw of 3.03X 104The dispersion coefficient was 1.17, and since a polymer of polystyrene was used as a standard curve, there was a certain error in the calculated molecular weight from the actual.
4. Preparation of hydroxychloroquine amphiphilic polymer prodrug nanoparticle PHCQ-NP
Dissolving 20mg of hydroxychloroquine amphiphilic polymer prodrug in 2mL of dimethyl sulfoxide, slowly dripping into deionized water with the volume of 4 times, stirring for 10 minutes, and dialyzing by using a 3500Da cellulose acetate semipermeable membrane to remove the dimethyl sulfoxide to obtain the hydroxychloroquine amphiphilic polymer prodrug nanoparticle, which is named as PHCQ-NP.
As shown in FIG. 6, the average particle size of the nanoparticles PHCQ-NP was about 68nm as measured by a dynamic light scattering apparatus.
As shown in FIG. 7, the morphological characteristics of PHCQ nanoparticles are characterized by a transmission electron microscope, and a transmission electron microscope image shows that the nanoparticles have an obvious double-layer vesicle structure and uniform particle size distribution of about 60-70 nm.
The prepared hydroxychloroquine amphiphilic polymer prodrug has a disulfide bond, and the disulfide bond has the characteristic of reduction response, so that the in-vitro response type release behavior of the drug is researched.
The specific method comprises the following steps: putting a certain volume of nanoparticles on a 3500Da cellulose acetate semipermeable membrane, wherein the outside of the semipermeable membrane is 40mL of PBS solution or 10mM of Dithiothreitol (DTT) PBS solution, taking 200 μ L of the solution outside the semipermeable membrane at a specific time, determining the concentration of hydroxychloroquine by using high performance liquid chromatography, and the release behavior is shown in figure 8.
5. Pharmacokinetics research of hydroxychloroquine amphiphilic polymer prodrug nanoparticle PHCQ-NP takes 6 ICR mice (weight is about 25g) with 6-8 weeks, each group comprises 3 mice, PHCQ-NP and hydroxychloroquine sulfate are respectively injected through tail vein, 5% glucose is added into the injection to prepare isotonic solution, the injection amount is 200 muL, the administration dose is hydroxychloroquine equivalent dose of 40mg/kg, 3-4 drops of blood are respectively taken through eyeholes at 2min, 30min,1h, 2h, 6h, 11.5h and 24h, 50 muL of the blood is sucked and added into a centrifugal tube of 0.1N NaOH with the same volume, and the mixture is uniformly mixed. And putting the blood sample into a 37 ℃ oven for incubation for 48h to ensure that the hydroxychloroquine is completely broken from the polymer, and after the incubation is finished, adding 400 mu L of acetonitrile into each centrifuge tube, and performing ultrasonic treatment for 30 min. Centrifuging at 14,800rpm for 10min, collecting supernatant 200 μ L, adding 200 μ L of 0.1N trifluoroacetic acid water solution, filtering with 0.22 μm organic phase filter head, measuring hydroxychloroquine concentration in the sample by high performance liquid chromatography, measuring the drug-time curve as shown in FIG. 9a, and analyzing pharmacokinetic parameters by DAS2.0 software, the result is shown in FIG. 9 b.
One of the characteristics of the nano-drug is that the nano-drug can significantly prolong the in vivo circulation time of the small molecule drug, as shown in fig. 9a, the in vivo circulation time of the hydroxychloroquine polymer nanoparticle PHCQ-NP is significantly longer than that of the small molecule hydroxychloroquine, and the concentration of PHCQ-NP in blood is even higher than that of the small molecule PHCQ-NP 3min after the hydroxychloroquine injection 24h after the injection. Pharmacokinetic parameters were analyzed using DAS2.0 software using the statistical moment method, and PHCQ-NP increased the area under the curve (AUC) 89-fold over 24 hours in the drug-time curve when the injected hydroxychloroquine equivalent dose was 40mg/kg, as shown in FIG. 9 b. (Note: FIG. 9a is a drug-time curve; FIG. 9b is a statistical moment parameter from DAS2.0 software analysis, AUC: area under the curve, an important parameter for calculating relative bioavailability; MRT: mean residence time; VRT, variance of residence time; CmaxPeak concentration).
In the embodiment, the surface of the nanoparticle is introduced with a methoxy polyethylene glycol block, the methoxy polyethylene glycol block has the capacity of preventing the nano-drug from being identified by a reticuloendothelial system, and the hydroxychloroquine is bonded on the polymer through a chemical bond, so that the coated drug can exist in the inner core of the nanoparticle more stably than the coated drug, and the hydroxychloroquine polymer nanoparticle can remarkably prolong the circulation time of hydroxychloroquine and improve the pharmacokinetic behavior of the hydroxychloroquine.
Claims (3)
1. The hydroxychloroquine amphiphilic polymer prodrug is characterized in that a hydroxychloroquine polymer is taken as a hydrophobic end, and polyethylene glycol monomethyl ether is taken as a hydrophilic end; the hydrophilic end and the hydrophobic end are polymerized in a mode of forming degradable chemical bonds through reversible addition-fragmentation chain transfer polymerization;
the preparation method of the hydroxychloroquine amphiphilic polymer prodrug comprises the following steps:
(1) adding an acryloyl chloride compound, an acrylic anhydride compound or a hydroxyethyl acrylate compound and free hydroxychloroquine into an organic solvent, and obtaining hydroxychloroquine compound monomer structures shown in formulas II and III under the synergistic action of a condensation reagent and an acylation catalyst;
(2) dissolving polyethylene glycol monomethyl ether and a micromolecule chain transfer agent PETTC into an organic solvent, and reacting under the synergistic action of a condensation reagent and an acylation catalyst to obtain the polyethylene glycol monomethyl ether-chain transfer agent macromolecular chain transfer agent with the structure shown in formula IV:
n is polymerization degree, and n is 22-1136;
(3) carrying out reversible addition-fragmentation chain transfer polymerization on hydroxychloroquine compound monomers shown in formulas II and III obtained in the step (1) and a macromolecular chain transfer agent of a polyethylene glycol monomethyl ether-chain transfer agent under the action of an initiator to generate the hydroxychloroquine amphiphilic polymer prodrug, wherein the polymerization temperature is 60-80 ℃; the polymerization degree of the hydroxychloroquine compound monomer is more than 1 and less than or equal to 100.
2. The hydroxychloroquine amphiphilic polymeric prodrug of claim 1, wherein said nanoparticles are formed by self-assembly in deionized water, and wherein said method for forming nanoparticles by self-assembly comprises dialysis, solvent evaporation, thin film hydration or co-precipitation.
3. The nanoparticle of claim 2, wherein the nanoparticle has a particle size in the range of 20nm to 300 nm.
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